Statin use and risk of liver cancer: Evidence from two population-based studies

Epidemiological studies of statin use and liver cancer risk have produced conflicting results. We examined the association between statin use and risk of primary liver cancer in two large independent study populations taking account of important covariates and main indications of statins such as high cholesterol and chronic liver disease. We performed a nested case–control study within the Scottish Primary Care Clinical Informatics Unit (PCCIU) database. Five controls were matched to cases with primary liver cancer and we used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations with statin use. We also conducted a prospective cohort study within the UK Biobank using self-reported statin use and cancer-registry recorded primary liver cancer outcomes. Cox regression was used to calculate hazard ratios (HRs) and 95% CIs. In the PCCIU case–control analysis, 434 liver cancer cases were matched to 2,103 controls. In the UK Biobank cohort, 182 out of 475,768 participants developed incident liver cancer. Statin use was associated with 39% lower risk of liver cancer in the PCCIU (adjusted OR 0.61, 95% CI 0.43–0.87). When we examined specific subtypes of liver cancer in the UK Biobank, statin use was associated with lower risk of hepatocellular carcinoma (HCC; adjusted HR, 0.48; 95% CI, 0.24–0.94) but not intrahepatic bile duct carcinoma (IBDC; adjusted HR, 1.09; 95% CI, 0.45–2.64). In conclusion, we found a consistent inverse relationship between statin use and risk of primary liver cancer which was only seen for HCC but not IBDC.     

Statin use and risk for ovarian cancer: a Danish nationwide case–control study

Background:

Limited data suggest that statin use reduces the risk for ovarian cancer.

Methods:

Using Danish nationwide registries, we identified 4103 cases of epithelial ovarian cancer during 2000–2011 and age-matched them to 58 706 risk-set sampled controls. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for epithelial ovarian cancer overall, and for histological types, associated with statin use.

Results:

We observed a neutral association between ever use of statins and epithelial ovarian cancer risk (OR=0.98, 95% CI=0.87–1.10), and no apparent risk variation according to duration, intensity or type of statin use. Decreased ORs associated with statin use were seen for mucinous ovarian cancer (ever statin use: OR=0.63, 95% CI=0.39–1.00).

Conclusions:

Statin use was not associated with overall risk for epithelial ovarian cancer. The inverse association between statin use and mucinous tumours merits further investigation.     

Risk factors for lung cancer among Canadian women who have never smoked

Risk factors for lung cancer among women who had never smoked were assessed in a case-control study of 161 newly diagnosed histologically confirmed cases and 483 population controls between 1994 and 1997 in eight Canadian provinces. Measurement included socio-economic status, smoking habits, alcohol use, diet, residential and occupational histories and exposure to environmental tobacco smoke (ETS). Dose-response associations were observed for consumption of tea, adjusted odds ratios (ORs) 0.6 (95% confidence interval (CI) = 0.3-0.9) for 1-7 cups per week and 0.4 (95% CI = 0.2-0.7) for > or = 8 cups per week (P = 0.0008), and smoked meat, adjusted ORs 1.3 (95% CI = 0.8-2.3) for 0.5 slice per week and 2.1 (95% CI = 1.1-4.0) for >0.5 slice per week (P = 0.02). Regular use of shortening in cooking was also related to lung cancer. Increased ORs with borderline significance were found for total consumption of meat, eggs or French fries and fried potatoes. Passive exposure to ETS at home (or at work) may be associated with lung cancer risk among never-smoker women; the adjusted ORs were 0.7 (95% CI = 0.2-2.3), 1.2 (95% CI = 0.4-3.2), 1.5 (95% CI = 0.5-4.0) for 1-16, 17-30, and 31 or more years of combined residential and/or occupational ETS exposure, respectively, with a similar pattern for smoker-years of ETS exposure.     

Statin use and breast cancer risk in a large population-based setting.

BACKGROUND: Mechanistic studies suggest that 3-hydroxy-3-methylglutaryl CoA inhibitors (statins) reduce the risk of breast cancer. Observational studies offer mixed results. METHODS: To evaluate the relation between statin use and breast cancer risk, we conducted a cohort study among women ages 45 to 89 years within an integrated health care delivery system. Information on statin use and covariates were obtained from automated databases. We identified breast cancer cases through the Surveillance, Epidemiology, and End Results registry. We used Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (95% CI) for invasive breast cancer among statin users compared with nonusers. RESULTS: Among 92,788 women studied from 1990 to 2004, median follow-up time was 6.4 years, and 2,707 breast cancer cases were identified. During the study period, 7.4% of women used statins for at least 1 year, and the median duration of use was 3.1 years. We found no difference in breast cancer risk among statin users (HR, 1.07; 95% CI, 0.88-1.29) compared with nonusers. Risk of breast cancer did not differ by duration of use (1-2.9, 3-4.9, or >or=5 years) or hydrophobic statin use. We found a suggestive increased risk of breast cancer among statin users of >or=5 years (HR, 1.27; 95% CI, 0.89-1.81 for any statins and HR, 1.47; 95% CI, 0.89-2.44 for hydrophobic statins) and of estrogen receptor-negative tumors with increasing duration of statin use (1-2.9 years: HR, 1.33; 95% CI, 0.64-2.77; 3-4.9 years: HR, 1.68; 95% CI, 0.72-3.92; >or=5 years: HR, 1.81; 95% CI, 0.75-4.36). CONCLUSION: This study does not support an association between statin use and breast cancer risk.     

High Receipt of Statins Reduces the Risk of Lung Cancer in Current Smokers With Hypercholesterolemia: The National Health Insurance Service–Health Screening Cohort

BackgroundThe incidence and mortality of lung cancer have risen steadily with the increasing popularity of tobacco smoking. Observational studies suggest that statins, which are widely used to lower cholesterol, may prevent lung cancer; however, other studies have produced conflicting results. We investigated the effect of statin receipt on lung cancer risk in Korean men according to smoking status.Patients and MethodsWe collected data from the 2002-2015 National Health Insurance Service–National Health Screening Cohort (NHIS-HEALS). We included a total of 16,588 men in the final analysis. We classified the participants as having high or low statin receipt or as not receiving statins. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer risk by statin receipt after adjusting for potential confounders.ResultsWe identified 363 patients with a new diagnosis of lung cancer from 2005 to 2015. Compared to participants who did not receive statins, high statin receipt resulted in a reduced lung cancer risk (HR = 0.64; 95% CI, 0.47, 0.85) after adjustment for confounders. Among current smokers, the fully adjusted HR for high statin receipt compared to those who did not receive statin therapy was 0.50 (95% CI, 0.32, 0.79).ConclusionHigh statin receipt was associated with lower risk of lung cancer in Korean men with hypercholesterolemia, especially current smokers.     

The interaction between microsomal epoxide hydrolase polymorphisms and cumulative cigarette smoking in different histological subtypes of lung cancer.

Microsomal epoxide hydrolase (mEH) is involved in the metabolism of environmental and tobacco carcinogens. Smaller studies found inconsistent results in the relationship between mEH polymorphisms and lung cancer risk. We investigated the two polymorphisms of mEH in 974 Caucasian lung cancer patients and 1142 controls using PCR-RFLP techniques. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between mEH genotypes and lung cancer risk. The adjusted odds ratio (OR) of the very low activity genotype versus that of other genotypes combined was 1.00 [95% confidence interval (CI), 0.74-1.34]. However, gene-environment interaction analyses revealed that the ORs decreased as cumulative smoking (defined as square root of pack-years) increased. When pack-years = 0, the OR was 1.89 (95% CI, 1.08-3.28). When pack-years = 28.5, the OR was 1.00 (95% CI, 0.76-1.32), and when pack-years = 80, the OR decreased to 0.65 (95% CI, 0.42-1.00). When cases were stratified according to histological subtypes, the interaction between mEH genotype and cumulative smoking was statistically significant (P < 0.01) for the 222 squamous cell carcinoma cases, whereas it was not significant (P = 0.18) for the 432 adenocarcinoma cases. In conclusion, cumulative cigarette smoking plays a pivotal role in the association between mEH polymorphisms and lung cancer risk, altering the direction of risk (in the case of the very low activity genotype) from a risk factor in nonsmokers to a relatively protective factor in heavy smokers.     

Genetic polymorphisms in N-acetyltransferase-2 and microsomal epoxide hydrolase, cumulative cigarette smoking, and lung cancer.

N-acetyltrasferase-2 (NAT2) and microsomal epoxide hydrolase (mEH) are polymorphic genes that metabolize different tobacco carcinogens. Smaller studies found inconsistent relationships between NAT2 or mEH polymorphisms and lung cancer risk. To determine whether there is gene-environment interaction between NAT2 polymorphisms, alone or in combination with mEH polymorphisms, and cumulative smoking exposure in the development of lung cancer, we conducted a case control study of 1115 Caucasian lung cancer patients and 1250 spouse and friend controls. The results were analyzed using generalized additive models and logistic regression, adjusting for relevant covariates. There was no overall relationship between NAT2 genotype and lung cancer risk; the adjusted odds ratio (OR) of the rapid versus slow acetylator genotypes was 0.96 [95% confidence interval (CI), 0.79-1.16]. However, gene-environment interaction analyses revealed that the adjusted ORs increased significantly as pack-years increased. For nonsmokers, the fitted OR was 0.66 (95% CI, 0.44-0.99), whereas for heavy smokers (80 pack-years), the OR increased to 1.22 (95% CI, 0.89-1.67). When comparing the extreme genotype combinations of the NAT2 rapid acetylator, higher mEH activity genotype to the NAT2 slow acetylator, and very low mEH activity genotype, the corresponding ORs at 0 and 80 pack-years were 0.30 (95% CI, 0.14-0.62) and 2.19 (95% CI, 1.26-3.81), respectively. Results were similar with ORs derived from stratified models. In conclusion, NAT2 rapid acetylator genotypes are protective against lung cancer in nonsmokers but are risk factors in heavy smokers. The joint effects of NAT2 and mEH polymorphisms are consistent with an independent, additive effect of these two genes, modified by smoking history.     

Statin use and prostate cancer risk in a large population-based setting

BACKGROUND: Statins are a commonly used cholesterol-lowering drug, which also have the potential to affect cancer risk and progression. Results from previous studies offer mixed conclusions. METHODS: To evaluate the relation between statin use and prostate cancer risk, we conducted a retrospective cohort study during 1 January 1990 to 31 August 2005 among men 45-79 years receiving care within Group Health, an integrated healthcare delivery system. Information on statin use and covariates were obtained from health plan databases. We identified incident prostate cancer cases through the Surveillance, Epidemiology, and End Results cancer registry. We used Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for prostate cancer among statin users compared to non-users. RESULTS: Among 83,372 men studied, median follow-up time was 5.7 years and 2,532 prostate cancer cases were identified. About 14.4% used statins over the study period and median duration of use was 3.3 years. Compared to non-users, hydrophobic statin users had a reduced risk of prostate cancer (HR = 0.79; 95% CI, 0.66-0.94), and results are suggestive of a reduced risk among ever users of statins (HR = 0.88; 95% CI, 0.76-1.02) and hydrophilic statin users (HR = 0.67; 95% CI, 0.33-1.34). There was no trend in risk by duration of statin use, and no association between statin use and cancer aggressiveness, stage, or grade. CONCLUSION: Overall, this study does not support an associated between statin use and prostate cancer but a reduced risk cannot be ruled out.     

Polymorphisms in the DNA repair genes XRCC1 and ERCC2, smoking, and lung cancer risk.

XRCC1 (X-ray cross-complementing group 1) and ERCC2 (excision repair cross-complementing group 2) are two major DNA repair proteins. Polymorphisms of these two genes have been associated with altered DNA repair capacity and cancer risk. We have described statistically significant interactions between the ERCC2 polymorphisms (Asp312Asn and Lys751Gln) and smoking in lung cancer risk. In this case-control study of 1091 Caucasian lung cancer patients and 1240 controls, we explored the gene-environment interactions between the XRCC1 Arg399Gln polymorphism, alone or in combination with the two ERCC2 polymorphisms, and cumulative smoking exposure in the development of lung cancer. The results were analyzed using logistic regression models, adjusting for relevant covariates. Overall, the adjusted odds ratio (OR) of XRCC1 Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was 1.3 [95% confidence interval (CI), 1.0-1.8]. Stratified analyses revealed that the ORs decreased as pack-years increased. For nonsmokers, the adjusted OR was 2.4 (95% CI, 1.2-5.0), whereas for heavy smokers (>/=55 pack-years), the OR decreased to 0.5 (95% CI, 0.3-1.0). When the three polymorphisms were evaluated together, the adjusted ORs of the extreme genotype combinations of variant alleles (individuals with 5 or 6 variant alleles) versus wild genotype (individuals with 0 variant alleles) were 5.2 (95% CI, 1.7-16.6) for nonsmokers and 0.3 (95% CI, 0.1-0.8) for heavy smokers, respectively. Similar gene-smoking interaction associations were found when pack-years of smoking (or smoking duration and smoking intensity) was fitted as a continuous variable. In conclusion, cumulative cigarette smoking plays an important role in altering the direction and magnitude of the associations between the XRCC1 and ERCC2 polymorphisms and lung cancer risk.     

Factors associated with human small aggressive non small cell lung cancer.

BACKGROUND: Some non-small cell lung cancers (NSCLC) progress to distant lymph nodes or metastasize while relatively small. Such small aggressive NSCLCs (SA-NSCLC) are no longer resectable with curative intent, carry a grave prognosis, and may involve unique biological pathways. This is a study of factors associated with SA-NSCLC. METHODS: A nested case-case study was embedded in the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. SA-NSCLC cases had stage T1, N3, and/or M1 NSCLC (n = 48) and non-SA-NSCLC cases had T2 to T3, N0 to N2, and M0 NSCLC (n = 329). Associations were assessed by multiple logistic regression. RESULTS: SA-NSCLCs were associated with younger age at diagnosis [odds ratio (OR)(>or=65 versus <65), 0.44; 95% confidence interval (95% CI), 0.22-0.88], female gender, family history of lung cancer, and the interaction gender*family history of lung cancer and were inversely associated with ibuprofen use (OR(yes versus no), 0.29; 95% CI, 0.11-0.76). The ORs for associating gender (women versus men) with SA-NSCLC in those with and without a family history of lung cancer were 11.76 (95% CI, 2.00-69.22) and 1.86 (95% CI, 0.88-3.96), respectively. These associations held adjusted for histology and time from screening to diagnosis and when alternative controls were assessed. CONCLUSION: SA-NSCLC was associated with female gender, especially in those with a family history of lung cancer. If these exploratory findings, which are subject to bias, are validated as causal, elucidation of the genetic and female factors involved may improve understanding of cancer progression and lead to preventions and therapies. Ibuprofen may inhibit lung cancer progression.     

DNA repair gene XPC genotypes/haplotypes and risk of lung cancer in a Chinese population

DNA repair is central to normal cellular functions, and polymorphisms of DNA repair genes may cause variation in DNA repair capacity in the general population. Newly identified polymorphisms of xeroderma pigmentosum group C (XPC), one of the nucleotide excision repair genes, were shown to contribute to genetic susceptibility to cancer. In this study, we hypothesized that 2 exonic variants C499T and A939C and their haplotypes in XPC are associated with lung cancer risk. To test this hypothesis, we performed a case-control study of 320 histologically confirmed lung cancer patients and 322 age and sex frequency-matched cancer-free controls in a Chinese population. Multivariate logistic regression analyses revealed that the risks [adjusted odds ratios (ORs) and 95% confidence intervals (CIs)] associated with the XPC variant genotypes were 1.57 (95% CI = 1.13-2.19) for 499CT/TT and 1.21 (95% CI = 0.87-1.69) for 939AC/CC compared with the 499CC and 939AA wild-type homozygotes, respectively. Individuals with both putative risk genotypes (499CT/TT and 939AC/CC) had a greater risk of lung cancer (adjusted OR = 2.37; 95% CI = 1.33-4.21) compared with individuals with both wild-type genotypes (499CC and 939AA). When we performed the haplotype analysis and assumed the XPC 499T and 939C as risk alleles, the adjusted ORs increased as the number of variants in the haplotype genotypes increased (p(trend) < 0.001). In the stratified analysis, the greatest risk was found in smokers having the combined variant genotypes (adjusted OR = 7.36; 95% CI = 3.19-17.00) compared with nonsmokers having both wild-type genotypes and in smokers with 2 or 3 haplotype variants (adjusted OR = 7.27; 95% CI = 3.37-15.68) compared with nonsmokers having 0 haplotype variant. These findings indicate that XPC exonic variants may contribute to the risk of lung cancer in the Chinese population, and these variant genotypes may modulate the risk of lung cancer associated with smoking.     

Statins are associated with reduced risk of gastric cancer: a systematic review and meta-analysis

BackgroundSeveral observational studies have shown that statins may modify the risk of gastric cancer (GC). We carried out a systematic review and meta-analysis of studies evaluating the effect of statins on GC risk.Patients and methodsWe conducted a systematic search of multiple databases up to December 2012. Studies that evaluated exposure to statins, reported GC outcomes and odds ratio (OR) or provided data for their estimation were included in the meta-analysis. Pooled OR estimates with 95% confidence intervals (CIs) were calculated using the random-effects model.ResultsEleven studies (eight observational, three post-hoc analyses of 26 clinical trials) reporting 5581 cases of GC were included. Meta-analysis showed a significant 32% reduction in GC risk with statin use (adjusted OR, 0.68; 95% CI, 0.51–0.91). After exclusion of one study which was contributing to considerable heterogeneity, a significant 16% reduction in GC risk was a more conservative, consistent estimate (adjusted OR, 0.84; 95% CI, 0.78–0.90). This chemopreventive association was present in both Asian (adjusted OR, 0.68; 95% CI, 0.53–0.87) and Western population (adjusted OR, 0.86; 95% CI, 0.79–0.93).ConclusionsMeta-analysis of studies supports a protective association between statin use and GC risk, in both Asian and Western population, in a dose-dependent manner.     

Serum insulin-like growth factors, insulin-like growth factor-binding protein-3, and risk of lung cancer death: a case-control study nested in the Japan Collaborative Cohort (JACC) Study.

To elucidate the roles of insulin-like growth factors (IGFs) in the development of lung cancer, we conducted a case-control study nested within the Japan Collaborative Cohort Study. Serum samples were collected at baseline from 39140 men and women between 1988 and 1990. We measured serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in 194 case subjects who subsequently died from lung cancer during an 8-year follow-up and in 9351 controls. The odds ratios (ORs), adjusted for smoking and other covariates, were smaller with higher levels of IGF-II and IGFBP-3. The ORs across quartiles were 0.41 (95% confidence interval [CI], 0.27-0.63), 0.47 (0.31-0.71), and 0.67 (0.46-0.98) for IGF-II (trend P=0.018), and 0.55 (95% CI, 0.37-0.81), 0.54 (0.36-0.82), and 0.67 (0.45-1.01) for IGFBP-3 (trend P=0.037). These peptides were not independently related to lung cancer risk when mutually adjusted. The risk was increased in the highest vs. the lowest quartile of IGF-I only after controlling for IGFBP-3 (OR, 1.74; 95% CI, 1.08-2.81). Limiting subjects to those followed for 3 years strengthened the negative associations of IGF-II and IGFBP-3, whereas the ORs for IGF-I generally decreased. A higher level of circulating IGFBP-3 and / or IGF-II may decrease lung cancer risk. Elevated serum IGF-I may increase the risk, but this could partly be attributable to latent tumors.     

Sequence variations in the DNA repair gene XPD and risk of lung cancer in a Chinese population

Variation in DNA repair capacity, which is believed to be largely determined by genetic traits, is linked to risk of certain cancers. The Asp312Asn and Lys751Gln polymorphisms in the xeroderma pigmentosum complementary group D (XPD) gene may alter DNA repair capacity. We thus examined the hypothesis that these 2 XPD polymorphisms are associated with risk of lung cancer via a large hospital-based, case-control study among Chinese. The study subjects consisted of 1,006 patients with primary lung cancer and 1,020 age- and sex-matched population controls. XPD genotypes were determined using PCR-RFLP techniques, and the associations between genotypes and risk of lung cancer were estimated by odds ratios (ORs) and their 95% confidence intervals (CIs) calculated by unconditional logistic regression. Subjects homozygous for the 312Asn/Asn genotype had an increased risk of lung cancer (adjusted OR = 10.33, 95% CI = 1.29-82.50) compared with subjects homozygous for the 312Asp/Asp genotype. The 751Gln/Gln genotype was also associated with increased risk for the cancer compared with the 751Lys/Lys genotype (adjusted OR = 2.71, 95% CI = 1.01-7.24). Stratification analysis revealed that the increased risk was mainly confined to lung squamous cell carcinoma, with the ORs being 20.50 (95% CI = 2.25-179.05) for the 312Asn/Asn genotype and 4.24 (95% CI = 1.34-13.38) for the 751Gln/Gln genotype, respectively. Haplotype analysis with the 2 polymorphisms suggested these polymorphisms might be in linkage disequilibrium with a different causative locus or act together with other functional variants in or close to the XPD locus.     

Long-term use of cholesterol-lowering drugs and cancer incidence in a large United States cohort

HMG-coA reductase inhibitors, commonly known as statins, account for the great majority of cholesterol-lowering drug use. However, little is known about the association between long-term statin use and incidence of most types of cancers. We examined the association between long-term use of cholesterol-lowering drugs, predominantly statins, and the incidence of ten common cancers, as well as overall cancer incidence, among 133,255 participants (60,059 men and 73,196 women) in the Cancer Prevention Study II Nutrition Cohort during the period from 1997 to 2007. Multivariate Cox proportional hazards regression was used to estimate relative risks (RR). Current use status and duration of use were updated during follow-up using information from biennial follow-up questionnaires. Current use of cholesterol-lowering drugs for five or more years was not associated with overall cancer incidence (RR = 0.97, 95% CI = 0.92-1.03), or incidence of prostate, breast, colorectal, lung, bladder, renal cell, or pancreatic cancer but was associated with lower risk of melanoma (RR = 0.79, 95% CI = 0.66-0.96), endometrial cancer (RR = 0.65, 95% CI = 0.45-0.94), and non-Hodgkin lymphoma (NHL; RR = 0.74, 95% CI = 0.62-0.89). These results suggest that long-term use of statins is unlikely to substantially increase or decrease overall cancer risk. However, associations between long-term statin use and risk of endometrial cancer, melanoma, and NHL deserve further investigation.     

Association of regular aspirin use and breast cancer risk

Of the limited number of epidemiological investigations on aspirin (and other nonsteroidal anti-inflammatory drugs) and breast cancer, the majority observe a protective role, yet only a few report dose-response effects for frequency or duration of use. We studied aspirin use among 1,478 breast cancer patients diagnosed from 1982 to 1998, and 3,383 cancer-free hospital controls at the Roswell Park Cancer Institute. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. Compared to never use,both regular (> or =1 tablet per week for > or =1 year) and occasional use were inversely associated with breast cancer (adjusted OR = 0.84, 95% CI 0.64-0.97; adjusted OR = 0.80, 95% CI 0.67-0.96, respectively). Among regular users, an inverse trend was found for number of tablets consumed per week (1, 2-6, or > or =7) with corresponding ORs of 0.95, 0.80, and 0.74 (P(trend) = 0.01). Daily use spanning 10 or more years was associated with a more pronounced reduction in risk (P(trend) = 0.005). Our findings corroborate the growing body of observational evidence that regular aspirin use may be associated with reduced risk of breast cancer.     

Statin use and the risk of prostate cancer: A metaanalysis of 6 randomized clinical trials and 13 observational studies

Statins have been suggested to prevent prostate cancer. Our aim was to examine statin use in relation to both total prostate cancer and the more clinically important advanced prostate cancer, through a detailed metaanalysis of the epidemiologic studies published on the subject in peer-reviewed literature. A comprehensive search for articles published up to November 2007 was performed, reviews of each study were conducted and data were abstracted. Prior to metaanalysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using the random-effects model. Subgroup and sensitivity analyses were also performed. Nineteen studies [6 randomized clinical trials (RCTs), 6 cohort and 7 case-control studies] contributed to the analysis. There was no evidence of an association between statin use and total prostate cancer among either RCTs (RR = 1.06, 95% CI: 0.93-1.20) or the observational studies (RR = 0.89, 95% CI: 0.65-1.24). However, high heterogeneity was detected among the observational studies. Moreover, long-term statin use did not significantly affect the risk of total prostate cancer (RR = 0.93, 95% CI: 0.77-1.13). In contrast, synthesis of the available reports that had specifically examined statin use in relation to advanced prostate cancer indicated a protective association (RR = 0.77, 95% CI: 0.64-0.93). Our results do not support the hypothesis that statins reduce the risk of total prostate cancer. However, further research is required to investigate whether the particular association of statin use with lower risk of advanced prostate cancer is indeed causal.